It is a gray building, at the end of the Croix-Rousse hospital, accessible by a hidden footbridge. Lyon’s national reference center (CNR) is home to one of the four French high-throughput sequencing poles (1) mobilized against the coronavirus epidemic. This is where scientists sequence or “read” samples from patients to detect and analyze variants.
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Two situations are of particular interest to experts: clusters and vaccine failures. In the first case, sequencing makes it possible to know whether a cluster is due to a new version of the coronavirus and which one. In the second, monitoring makes it possible to determine whether variants escape vaccines and to what extent.
A long process of preparing the samples
Before arriving at these results, the procedure is a matter of experts and state-of-the-art equipment. First of all, if the laboratory has not already done so, the sample must be rendered harmless by a chemical process. Then the sample preparation begins. You have to amplify the viral genome, just as you would increase the size of a text to make it more readable; cut it into smaller pieces, as one would return to the line to make a text more digestible; transform viral RNA into DNA, because the sequencer can only read that; and mark each piece of virus to be able to find which patient it corresponds to.
” This is crucial because the Regional Health Agency must be able to know which patient is infected with which variant. », Recalls Quentin Semanas, virological engineer. On the bench, a plastic plate barely larger than the palm of your hand has 384 wells. Each of these small cavities corresponds to a sample and therefore to a patient.
State-of-the-art machines for reading the genome
The preparation finished, the plate leaves a lower floor. Here ends the realm of biology and begins the world of computers and machines. An air-conditioned and noisy room accommodates the two sequencers of the Lyon hospital: one in the format of a large photocopier, the other of an office printer. It takes them 17 to 29 hours to “read” the genome of the virus, going through every basic piece of the genetic sequence.
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” The sequencer tells us “in position 1, I saw such and such an element at 95% so it must be that one”, and so on for all bases of the genome ”, summarizes Quentin Semanas. By putting the pieces back together in the correct order, scientists can see the genetic differences that the variants carry from the original virus.
France is catching up
In total, it takes a good week between the sample and the reading by the Lyon teams. The variant sequence is then integrated on the international Gisaid platform, which lists them all. ” We are very picky about the robustness of the data, we always analyze what the sequencer provides us instead of publishing it as is. », Says Quentin Semanas.
Long lagging behind in the global scientific contribution to sequencing, France has been catching up since the launch in January of the “Emergen” consortium. ” From a hundred sequences established each week at the end of 2020, we can now go up to 9,000 ”, figure Bruno Lina, at the head of the CNR.By the end of July, some private laboratories will join the four public centers. Goal ? Better cover the entire territory and be able to detect a variant as soon as it represents 2.5% of cases.
Interpreting the genetic differences of variants
But “ sequencing is not everything ”, recalls the specialist. “You have to be able to say whether such a mutation will lead to a more contagious form or not, he continues. Identifying variants without knowing their impact on the epidemic trajectory is useless. »A quest that comes from modeling and clinical observation. The British, for example, detected their Alpha variant as early as September, but they only realized its increased contagiousness in December, seeing it take up all the space.
In front of Bruno Lina, a large sheet of colored diagrams describes the consequences of certain mutations on the spike protein of the coronavirus. While this part of the virus, which attaches to our cells, has long been the subject of all attention, he believes that “ the mutations carried by the Delta variant in this area do not make it possible to explain such an increase in contagiousness ”. We will therefore still have to search.
Two methods of analysis
Sequencingis equivalent to reading the entire genome of the virus to see any changes from the original strain and to draw up a complete identity card of the variant.
Screening comes down to looking for a specific mutation, a “signature” for a given variant. It is a much faster technique but less exhaustive. If several variants have the same mutation, it does not make it possible to distinguish.